U.S. Pat. No. 4,681,893, discloses a route using resolution of the racemic product using R (+) α-methyl benzyl amine. U.S. Pat. No. 5,003,080 discloses a synthetic route for the preparation of the chiral form of atorvastatin. The patent discloses a process for the preparation of the lactone or its salts by coupling an ester of (4R)-6-(2-aminoethyl)-2,2-dialkyl-1,3-dioxane-3-acetate with 4-fluoro-α-[2-methyl-1-oxopropyl]γ-oxo-N-β-diphenylbenzenebutanearnide followed by deprotection and hydrolysis to give the product. The product suffers from the fact that ozonolysis is required as one of the steps for the synthesis of the amino ketal intermediate, which is hazardous for large scale preparation. The patent describes an alternate procedure wherein 4-fluoro-α-[2-methyl-1-oxopropyl]γ-oxo-N-β-diphenylbenzenebutaneamide is reacted with 3-amino propinaldehyde acetal followed by conventional procedures to give atorvastatin.
U.S. Pat. No. 5,216,174, No. 5,097,045, No. 5,103,024, No. 5,124,482, No. 5,149,837, No. 5,155,251, No. 5,245,047, No. 5,273,995, No. 5,248,793, and. No. 5,397,792 describe various minor modifications in the procedure for the preparation of atorvastatin calcium salt.
Synthesis of esters of (4R)-6-(2-aminoethyl)-2,2-dialkyl-1,3-dioxane-3-acetate is an important part of the preparation of atorvastatin calcium. U.S. Pat. No. 5,155,251 also discloses a synthetic route for the synthesis of (3R)-4-cyano-3-hydroxy butyric acid esters from (S)-3-hydroxy butyrolactone, which in turn is synthesized from a suitable carbohydrate substrate.
Other patents like U.S. Pat. Nos. 5,292,939, 5,319,110 and 5,374,773 disclose the preparation of 3,4-dihydroxybutyric acid. However, isolation of this highly water soluble compound or its lactone is not attempted.
Another multi step procedure starting from (S)-malic acid (J. org. Chem., 1981, 46, 4319) is reported. Esters of (S)-malic acid have also been used (Chem. Lett., 1984, 1389) for the synthesis of the hydroxy lactone involving BMS-NaBH4 reduction, followed by lactonization. While a six step procedure from D-isoascorbic acid is also reported (Syn., 1987, 570) but this process requires a silica gel chromatographic separation of the diastereomeric mixtures.
Optical resolution of the racemic hydroxylactones using lipase is disclosed in U.S. Pat. No. 5,084,392 but this method suffers from poor enantiomeric excess and loss of the other active isomer.
Thus, the above procedures involve cumbersome reaction conditions or expensive starting materials, reagents which are difficult to handle or hazardous for scale up, coupled with a multi step procedure which results in poor overall yield.
One object of the present invention is to disclose an inexpensive, simple and scalable route for the synthesis of atorvastatin. PCT pending application filed on Mar. 28, 2000 (PCT/IN00/00030) discloses a process for the synthesis but uses a different amino acid fragment for the condensation reaction to get atorvastatin calcium.